VEGF signaling and activation
The vascular endothelial growth factor (VEGF) family of ligands and receptors is
crucial for vascular development and neovascularization in physiological and pathological
processes in both embryo and adult . VEGFs denote a family of homodimeric
glycoproteins that currently consists of five members: VEGF-A, -B, -C, -D, and placenta
growth factor PLGF.
VEGFR-2 is a high-affinity receptor for
VEGF-A . The activated
VEGFR-2 binds Phospholipase C gamma 1
(PLC-gamma 1) That leads to the phosphorylation and
activation of this protein and results in hydrolysis of the membrane Phosphatidylinositol
(4,5)-bisphosphate (PtdIns(4,5)P2) and generation of the
second messengers 1,2-diacylglycerol (DAG) and inositol
DAG is a physiological activator of Protein kinase C beta 1
(PKC-beta), whereas IP3 binds
to a specific receptor present on the endoplasmic reticulum, resulting in the release of
intracellular stored Ca(2+) .
PKC-beta phosphorylates and activates V-raf-1 murine
leukemia viral oncogene homolog 1 (c-Raf-1) triggering
Mitogen-activated protein kinase kinase 1 (MEK1 (MAP2K1))/
Mitogen-activated protein kinase kinase 2(MEK2 (MAP2K2))/
Mitogen-activated protein kinase 3/1 (Erk (MAPK1/3))
signaling cascade. Erk
(MAPK1/3) can also be activated through
PKC/ Sphingosine kinase 1
(SPK1) pathway .
SPK1 is an enzyme which catalyses Spingosine
formation from Sphingosine. Decrease of
sphingosine concentration and increase of
1-phosphate leads to activation of V-Ha-ras
Harvey rat sarcoma viral oncogene homolog (H-Ras),
apparently through inhibition of Neurofibromin and RAS p21
protein activator 1 (p120GAP).
H-Ras in turn binds to and activates
c-Raf-1 leading to
(MAPK1/3) activation. Activated
Erk (MAPK1/3) activates by phosphorylation Jun
oncogene(c-Jun). The latter one forms a complex with V-fos
FBJ murine osteosarcoma viral oncogene homolog (c-Fos)
protein leading to DNA synthesis and cell proliferation .
DAG is also a physiological activator of
PKC-alpha which can signal through Conserved
helix-loop-helix ubiquitous kinase (IKK-alpha) and Inhibitor
of kappa light polypeptide gene enhancer in B-cells kinase beta
(IKK-beta) to I-kB/
NF-kB pathway. , .
NF-kB activates transcription of
Intercellular adhesion molecule 1 (ICAM1), Vascular cell
adhesion molecule 1 (VCAM1) and
VEGFR-2 also binds and activates
Phosphoinositide-3-kinase regulatory subunit (PI3K reg class
IA)  followed by the activation of catalytic subunits of
PI3K - PI3K cat class IA, which, in turn, results in an
increase in lipid Phosphatidylinositol (3,4,5)
(PtdIns(3,4,5)P3) and activation of V-akt murine thymoma
viral oncogene homolog 1 AKT(PKB). The
AKT(PKB) signaling pathway regulates cellular survival by
inhibiting pro-apoptotic pathways .
Brca1 represses the activity of
VEGF-A via ESR1 and
SP3 , .
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Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family.
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